Method of lowering blood pressure



United States Patent 3,487,154 METHOD OF LOWERING BLOOD PRESSURE Edward D. Coen, Media, Pa., assignor to Smith Kline & 'French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania lce treating the acetylated compound III with chlorosulfonic acid, aminating the resulting sulfonyl chloride IV with ammonia, methylarnine, or dimethylamine to give an amido sulfonamide V, and hydrolyzing the acetyl group with acid or base to give the amino sulfonamide I. The

NO Dlflwillg- Filed P 1967, 627,624 5 products are isolated as their hydrochloride salts if hy- Illt- A611 27/ 00 drochloric acid has been the hydrolytic agent, or the -S' 4 V 12 Chums salts are prepared by combining the basic product with a pharmaceutically acceptable acid according to conven- ABSTRACT OF THE DISCLOSURE tio lil tllll practice. d f F 1 h b f d I n ulfonamides e compoun s o ormu a I ave een oun to E: by of m aminoalkylbenzenes with chlorosulfonic acid and aminafizgggifi g gfg3253253 2232 g gg y g gsgi gg non wlth ammonia methylamme or dlmethylamme' kg., they lowered blood pressure from 10 to over 30 r mm. Hg for up to 5 days. Particularly active are This invention relates to a method of lowering blood pressure in mammals and to compositions therefor. In p'(2'am mPrPyl)benzenesulfonalmde particular, the invention relates to a method of lowering P'(2'am1nethy,1)benzenesulfonamlde blood pressure in a mammal comprising administering to P'Q'meFhYIammOethYI)benzenesulfonamlde a mammal certain benzenesulfonamide compounds or P(z'ammocyclfpropyl)benzenesulfonamldfa salts ther'eofi p-(2-methylam1nopropyl)benzenesulfonamide,

The compounds used in the method of the present inp(2'am{nPrPyD'Nmethylbenzenesulfonamlde vention are represented by the following structural for- P-(2-am%nPIPY1)N:N-dlmethylbeflzenesulfnamlde, and mula: p-(2-ammo-2-methylpropyl)benzenesulfonam1de.

The preferred compound for purposes of the present NSOz-(3HCNHR invention is dl p (Z-aminopropyl)benzenesulfonamide.

This compound has also been found to effectively lower I blood pressure in neurogenic hypertensive dogs when adwherein: ministered in daily oral doses of 20 mg./kg. In mice its LD has been determined to be 1872 mg./ kg. subcutaneeacl} R 15 yd methyl; ously and 5616 mg./kg. orally, and in rats greater than R1 5 hydrogen r y or together Wlth R2 18 y 3276 mg./kg. subcutaneously and 3990 mg./kg. orally.

- w t The compounds of Formula I are formulated for use R2 15 hydrogen or togethfil' With Rl-lS methyleneas hypotensive agents by combining them with standard Also usable in the method of the invention are h pharmaceutical excipients according to conventional pharmaceutically acceptable 'acid addition salts of the methods in Order to P p dosage units $11611 as tablets, compounds of Formula I. Included among these salts are capsules, or inlect'ablea In a the componem the hydrochloride, hydrobromide, sulfate, nitrate, maleate, 40 or S alt thereof 15 generally lncofpofatefi Into a solld tartrate acetate, benzoate, phosphate, and ethanedisulcarrier. Among the acceptable solid carriers are lactose, fonatei sucrose, magnesium stearate, stearic acid, starch, terra The compounds to beused inthe method of the alba, talc, calcium phosphate, gelatin, agar, pectin, and vention are either disclosed in the literature or are preacacla- A capsule Y be Prepared y Placmg the Pctlve paredby methods known or'described herein. p-(2-aminof p f e ther alone or incorporated mto a -ethyl)benzenesulfonamide is described in]. Am; Chem. Sohd F m a hard gelatm Capsule- A me-delay 3 62 2 99- 1940 (2 i 1)b lf material such as glyceryl monostearate or distearate, and, 2 1 l z alone or with a wax, may also be included. An injectable fgn id are described i J. d Chem 6, 519 1963 formulation may consist of a solution of the active compo- They and other compounds within the scope of Formula Dent Salt in Saline Solution, Purififid Water, I are preparable by starting with the readily available sugar solution, possibly with preservatives such as para- .phenyalkylamine H, protecting the amino group by acetbens added. The compositions thus prepared are adminylation, v istered orally or pa-renterally in doses of 50-500 mg.

- v R 1 1 R R R gnaw, aaaam V.

' II III "R" v R2 R R l R R1 R V Iv R i 2 l preferably 250-400 mg., 1 to 4 times daily. The optimum dosage will be determined on an individual basis taking into consideration the Weight of the recipient, degree of hypotensive effect desired, and other pertinent factors.

Certain of the compounds within the scope of Formula I possess asymmetric carbon atoms and thus can exist as racemic mixtures or as optically active d and l compounds. Since it has been found that hypotensive activity is possessed by both racemic and optically active forms, it is intended that the present invention be construed to include any of the possible racemic or optically active forms. The various optically active forms of the compounds are obtained preferably by using the appropriate optical isomer as starting material, or else by separating according to conventional techniques the racemic mixtures.

The following examples are intended to illustrate the preparation of the compounds and compositions used in the invention, but are not to be construed as limiting the scope thereof.

EXAMPLE 1 p- Z-aminopropyl -N-methylbenzenesulfonamide A carefully prepared mixture of 100 ml. of acetic anhydride and 25 g. of a-methylphenethylamine is heated on the steam bath for l-3 hours and the excess acetic anhydride evaporated. The residue of N-acetyl-a-methylphenethylamine is crystallized from aqueous alcohol or ether and melts at 92-93.

The above amide (20 g.) is added with stirring in several portions to a -fold excess by weight of chlorosulfonic acid, cooled in a dry ice-acetone bath. After the addition is complete, the reaction mixture is allowed to stand overnight at room temperature and then poured into a large excess of ice. The mixture is allowed to stand for several hours and the supernatant liquid decanted from the residual sulfonyl chloride. A 40% aqueous methylamine solution is then added, the mixture is then heated on the steam bath for about minutes and cooled The resulting oily p-(2-acetamidopropyl)-N-methylbenzenesulfonamide is crystallized with n-butanol-ether and melts at 95-97".

A suspension of 10 g. of the above sulfonamide in 100 ml. of conc. HCl-water (1:3) is refluxed for about 12 hours, cooled, filtered if needed and evaporated. Benzene (10 ml.) is added and evaporated off. The residual hydrochloride salt of the title product is crystallized from ethanol-ether and melts at 191-193".

EXAMPLE 2 p- (2-amino-2-methylpropyl) benzenesulfonamide A solution of 9.6 g. of the above sulfonamide in 100 ml. of 10% NaOH is refluxed for 18 hours, cooled, and acidified with concentrated HCl. The mixture is filtered and the filtrate evaporated to dryness in vacuo. The residue is extracted with hot ethanol, the extracts concentrated to a small volume, and ether added until no more salt precipitates. Filtration gives the hydrochloride salt of the title product, recrystallized from ethanol-ether, M.P. 255-257".

' EXAMPLE 3 p- (Z-methylaminopropyl benzenesulfonamide d-N-ot-dimethylphenethylamine is acetylated with acetic anhydride as described in Example 1 to give d-N-acetyl- N-a-dimethylphenethylamine.

This amide is allowed to react with chlorosulfonic acid according to the procedure of Example 1 and the resulting sulfonyl chloride treated with aqueous ammonia in place of methylamine as described therein to give d-p-(Z- N methylacetamidopropyl)henzenesulfonamide, recrystallized from acetone-hexane, M.P. 83-85 This sulfonamide (10 g.) is hydrolyzed with 10% NaOH as described in Example 2. The hydrochloride salt of the title product is recrystallized from ethanol-ether and decomposes at 232.

The dl-product is obtained in the same manner by preparing the acetamide, treating with chlorosulfonic acid and then ammonia to obtain the amide sulfonamide, M.P. 165-1 66" (from ethanol), and hydrolyzing the acetyl group to give the hydrochloride salt of the dl-product, M.P. 194-186 (from ethanol).

EXAMPLE 4 p- (Z-methylaminoethyl benzeneulfonamide N-methylphenethylamine is acetylated with acetic anhydride as described in Example 1 to give N-acetyl-N- methylphenethylamine.

This amide is allowed to react with chlorosulfonic acid according to the procedure of Example 1 and the resulting sulfonyl chloride treated with aqueous ammonia in place of methylamine as described therein to give p-(2-N- methylacetamidoethyl)benzenesulfonamide, M.P. 82-85 (from ethyl acetate).

This sulfonamide (25 g.) is refluxed overnight with 200 ml. of 1:1 concentrated HCl-water and evaporated in vacuo. The residue is triturated with ethanol and filtered, and the recovered hydrochloride recrystallized from ethanol or methanol-ether, M.P. 228-230".

EXAMPLE 5 p- (Z-aminocyclopropyl) benzenesulfonamide To a stirred suspension of g. of trans 2- phenylcyclopropylamine sulfate in 25 0 ml. of water is added g. of acetic anhydride. When all the solid has dissolved, a solution of 111 g. of sodium acetate trihydrate in 250 ml. of water is added. The solution is allowed to stand overnight and is extracted with methylene chloride. The extracts are dried and evaporated to give trans-N-acetyl-Z-phehylcyclopropylamine, M.P. 90- 91 (from benzene-hexane). I

To 20 g. of this amide in a Dry-Ice-acetone bath is added 200 ml. of chlorosulfonic acid. The mixture is kept at room temperature overnight, poured into 2 l. of ice, filtered or decanted, and the residue treated with aqueous ammonia and heated briefly on the steam bath. The mixture is filtered and allowed to cool, and the separated trans p (2 acetamidocyclopropyl)benzenesulfonamide. M.P. -176 (from ethanol-cyclohexane) obtained.

This sulfonamide (4 g.) is refluxed for 2 hours with 40 ml. of 10% HCl and evaporated. The residual hydrochloride of the title product is recrystallized from ethanol, M.P. 214-215".

EXAMPLE 6 A capsule for lowering blood pressure has the follow A tablet for lowering blood pressure has the following components:

p-(Z-aminopropyl)benzenesulfonamide hydrochloride 250 Magnesium stearate 2.5 Starch 15 Terra alba 150 Granulate with syrup or 5% gelatin solution terra alba q.s. ad 450 I claim:

1. A method of lowering blood pressure in a mammal requiring such treatment comprising administering to said mammal an effective amount of a compound of the formula:

4. A method as claimed in claim 3, where the compound is administered in a dose of 50-500 mg.

5. A method as claimed in claim 2, where the compound is p-(Z-aminoethyl)benzenesulfonamide or a pharmaceutically acceptable acid addition salt thereof.

6. A method as claimed in claim 2, Where the compound is p-(Z-methylaminoethyl)benzenesulfonamide or a pharmaceutically acceptable acid addition salt thereof.

7. A method as claimed in claim 2, where the compound is p-(2 methylaminopropyl) benzenesulfonamide or a pharmaceutically acceptable acid addition salt thereof.

8. A method as claimed in claim 2, where the compound is p-(Z-aminopropyl) N methylbenzenesulfom amide or a pharmaceutically acceptable acid addition salt thereof. v

9. A method as claimed in claim 2, where the compound is p-(2 aminopropyl) N,N dimethylbenzenesulfonamide or a pharmaceutically acceptable acid addition salt thereof.

10. A method as claimed in claim 2, where the compound is p-(2-amino-2-methylpropyl)benzenesulfonamide or a pharmaceutically acceptable acid addition salt thereof.

11. A tablet or capsule for lowering blood pressure comprising -500 mg. of p-(2-aminopropyl)benzenesulfonamide or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier therefor.

12. A tablet or capsule as claimed in claim 11, where the amount of p-(Z-aminopropyl)benzenesulfonamide is 25 0-400 mg.

References Cited.

Miller et al., J. Am. Chem. Soc. 62, pp. 2099-2103 (1940).

Holland et al., J. Med. Chem. 6, pp. 519-524 (1963).

ALBERT T. MEYERS, Primary Examiner S. I. FRIEDMAN, Assistant Examiner 

